The tumor suppressor p53 (protein expressed from TP53) has been shown to be downregulated in numerous cancers. The p53 protein exerts its tumor suppressive function acting primarily as a transcription factor, that controls the expression of a large and ever increasing number of target genes in response to a variety of signals (Beckerman and Prives (2010) Cold Spring Harbor Perspectives in Biology 2; Riley et al. (2008) Nat. Rev. Mol. Cell. Biol. 9: 402-412; Brady and Attardi (2010) J. Cell Sci. 123: 2527-2532. Well known outcomes are cell cycle arrest, DNA repair, apoptosis, but more recently p53 involvement in the induction of autophagy and regulation of metabolism and mitochodrial function have also been described (Vousden and Ryan (2009) Nat. Rev. Cancer, 9: 691-700; Gottlieb and Vousden (2010) 53. Regulation of Metabolic Pathways Cold Spring Harbor Perspectives in Biology 2).
The tumor suppressing protein p53 represents an underexplored therapeutic opportunity to develop new treatments with low host toxicity to reverse the abnormal metabolic and bioenergetic programs that are a hallmark feature of cancer. In this regard, mall molecule restoration of p53 function represents a exciting new approach, with the clinical emergence of MDM2 inhibitors like the spiro-oxindole MI-63 and other p53 reactivating drugs especially promising for the treatment of malignancies like breast cancer where up to 75% of all new cases express wildtype (wt) p53.
PIG6, also known as PRODH/POX, is among the apoptotic genes induced by p53 after adriamycin treatment (Polyak et al. (1997) Nature, 389: 300-305.). Since its discovery, evidence has been accumulating on the role that proline dehydrogenase, the protein encoded by the PRODH gene, could play in suppressing tumorigenesis, suggesting its contribution as an apoptosis effector through reactive oxygen species (ROS) induction (Donald et al. (2001) Cancer Res. 61: 1810-1815). Thus, for example, J W Phang's lab (NCI) identified PIG6 as mitochondrial proline oxidase/dehydrogenase (POX/PRODH) whose ROS production was thought to induce apoptosis and mediate tumor suppression.